Opiates and opioid peptides act by binding to specific recognition sites, or receptors. A number of different opioid receptor subtypes have been identified which mediate distinct pharmacological actions. Recent evidence now indicates that at least five of these receptor subtypes can mediate analgesia independently of each other. Furthermore, they act in different regions of the neuroaxis: mu1 and kappa3 supraspinally and mu2, kappa l and delta spinally. The importance of spinal/supraspinal interactions in morphine analgesia have long been known. We propose to extend these studies to the spinal/supraspinal interactions of the various subtypes. Microinjection studies also have identified important regions within the brain where morphine can elicit pain relief. We propose to examine the interactions of these selective sites with spinal mechanisms as well. Using this microinjection approach we now have observed synergistic analgesic interactions between the locus coerulus and the periaqueductal gray. Simultaneous administration of a partial agonist to both regions elicits analgesia which cannot be produced by injections to a single region regardless of the dose of drug. We plan to continue to characterize these supraspinal/supraspinal interactions. This microinjection model enables us to examine the intrinsic activity of opioids at mu l receptors. We also propose to study the roles of these various subtypes of opiate receptors in other opioid actions, particularly respiratory depression and inhibition of gastrointestinal transit. Finally, we hope to examine the interactions of nonopioid drugs upon opioid analgesia and other actions. Antidepressants and CCK antagonists have been used to potentiate opioid analgesia and we plan to examine these interactions with particular emphasis upon the opioid receptor subtype systems involved.